Severe morbidity and mortality are commonly associated with spinal cord injury (SCI). Patients who survive frequently live with paralysis and extremely reduced quality of life and productivity. The financial and emotional burdens to patients and their caregivers are enormous. There is currently no effective cure. This is largely because SCI often results in a permanent loss of neurons and the disruption of neural circuits. For a functional recovery after SCI, the key challenge is how to restore the disrupted neuronal circuits. The long-term goal of this proposed research is to develop an innovative therapeutic strategy for SCI by using patients' endogenous cells. In response to injury, astrocytes become reactive and proliferate to form glial scars. These scars are initially beneficial by preserving th integrity of cells surrounding the damaged site. However, their persistence is detrimental to neuronal repair. Glial scars not only form a physical barrier but also secrete inhibitors of axon growth that act on surviving neurons. We hypothesize that changing the fate of these scar- forming cells to neural progenitors and/or neurons might enable self-repair of the injured spinal cord in two ways: 1) by relieving the inhibition of axon growth of surviving neurons by glial scars and 2) by the formation of bridging neural circuits through converted new neurons. Our preliminary data shows that new neurons can be induced by the ectopic expression of a single transcription factor in the adult spinal cord. The major goals of this proposal are 1) to further examine the in vivo reprogramming process in the adult spinal cord, 2) to target several genetic and epigenetic pathways to enhance the reprogramming efficiency, and 3) to optimize the reprogramming process for neuronal survival, maturation and functional integration into the local neuronal circuitry. Results from this proposal may lead to a novel therapeutic strategy for SCI, which is to let the injured spinal cord repair itself using endogenous cells.